Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects

•ESL significantly decreased the exposure to simvastatin and simvastatin-β-hydroxyacid.•This effect is most likely mediated by an induction of CYP3A4 metabolism.•Dose adjustment of simvastatin may be required when used concomitantly with ESL.

SummaryObjectiveTo investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of simvastatin (SMV), a known CYP3A4 substrate, in healthy subjects.MethodsSingle centre, two-way cross-over, randomized, open-label study in 24 healthy volunteers. The volunteers received an oral single-dose of SMV 80 mg on two occasions (once administered alone and once after treatment with an oral once-daily dose of 800 mg of ESL for 14 days), separated by a wash-out period of 3 weeks or more. The analysis of variance (ANOVA) was used to test for differences between Test (SMV under co-administration with ESL) and Reference (SMV administered alone) treatments for AUC0−∞, AUC0−t and Cmax of SMV and SMV-acid.ResultsMean systemic exposure (AUC) measurements for both SMV and SMV-β-hydroxyacid (SMV-acid) were up to 54% lower during ESL use. The Test/Reference geometric mean ratios (GMR) (90% CI) for the AUC0−t of SMV and SMV-acid were 46% (38%; 55%) and 49% (44%; 55%), respectively. Mean peak concentrations (Cmax) of both SMV and SMV-acid were reduced by 60% and 41%, respectively, when SMV was administered with ESL.ConclusionsA significant effect of repeated ESL administration on the pharmacokinetics of SMV and its metabolite SMV-acid was observed. Therefore, dose adjustment of SMV may be required when used concomitantly with ESL, if a clinically significant change in lipids is noted.